Abstract 2570: Role of PPAR gamma in chemoprevention of renal cell carcinomas by omega-3 fatty acids

Abstract

Abstract Renal Clear Cell Carcinoma (RCC) is the tenth most prevalent cancer, accounting for 80% of all renal cancers. Recent results of a 15.3 year epidemiological study indicate that a diet of fatty fish offers significant protection against RCC, results which were attributed to omega-3 fatty acids. The question arises as to the molecular mechanisms by which such omega-3 fatty acids exert their protective effect. Our hypothesis is that omega-3 fatty acids exert their protective effects by activating Peroxisome Proliferator-Activated Receptors (PPARs), which in turn reduce the level of expression of Hypoxia Inducible Factor (HIF). The level of HIF increases as a consequence of mutations in the von Hippel Lindau (VHL) gene, which is key to the development of RCCs. In order to begin to examine this hypothesis, primary cultures of renal proximal tubule cells have been examined with regards to their growth responses to PPAR agonists (as the RCC is of renal proximal tubule origin). Fibrate drugs and thiazolidinediones (TZDs) have been identified which have a high affinity for two different classes of PPARs, PPAR alpha and PPAR gamma, respectively. We have observed that troglitazone, a PPAR gamma agonist, caused a 4-fold increase in growth a concentration range of 10-6 to 5 x 10-6 M. A physiologically produced PPAR gamma agonist, Prostaglandin J2 (PGJ2), was also growth stimulatory, albeit to a lesser extent. In contrast, fenofibrate, a PPAR alpha agonist, had no significant affect. In order to examine our hypothesis that PPAR gamma activation affects signaling through HIF, transient transfection studies were conducted with HRE-Luc, a HIF regulatory element/reporter construct. The level of expression of HRE-Luc increases during hypoxia, leading to metabolic changes that promote tumorigenesis. Our studies with HRE-Luc indicate that 5 x 10-6 M troglitazone reduces the increase in HRE-Luc gene expression by over 50%. Similarly, troglitazone prevented the increase in HIF which occurs under normoxia in the presence of the hydroxylase inhibitor dimethyloxalylglycine (DMOG). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2570. doi:1538-7445.AM2012-2570